Our laboratory's long-range goal is to develop new approaches to eradicate HIV-1. Unlike most viral infections, HIV-1 is able to overcome the host innate and adaptive immune response to establish a life long infection in nearly every infected person. Moreover, standard approaches to develop vaccines have not succeeded in providing protection from initial infection and antiviral drugs have not yet provided a cure. Thus, novel approaches are needed that will more effectively counteract the unique ability of HIV-1 to establish a persistent infection in nearly every host. We expect that a greater understanding of viral strategies will inform the design of therapeutic approaches that will result in prevention of infection, long-term remission or cure. As the next step towards this goal, the objective of this application is to understand how the HIV-1 accessory protein, Vpr, allows HIV-1 to evade innate immune responses. We have shown that Vpr counteracts a macrophage-specific Env degradation pathway in primary monocyte derived macrophages (MDM) and MDM-T cell co-cultures and that Vpr limits induction of interferon (IFN) gene expression following infection. Determining how Vpr evades these responses will provide crucial knowledge that may reveal approaches that will help clear infection. To accomplish this goal, we will test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: (1) Identify the IFN-induced macrophage-specific restriction factor that promotes Envelope degradation and (2) Determine how Vpr allows HIV to evade the innate immune response in macrophages. At the completion of these studies we expect to have identified the IFN-induced restriction factor and we expect to establish that Vpr interacts with host DNA repair proteins to limit sensing of DNA intermediates and innate immune responses in MDM. These outcomes are expected to have an important contribution to the field by identifying the pathways that are most important to target for anti-HIV drug development.